The Bone–Brain Axis: Novel Insights into the Bidirectional Crosstalk in Depression and Osteoporosis

Depression and osteoporosis frequently co-occur, presenting a significant and increasing clinical challenge, especially among older adults. Growing research highlights the bone-brain axis, a complex bidirectional communication network connecting the skeletal and central nervous systems, as a central mechanism linking these conditions. This review comprehensively examines the current knowledge of the molecular and cellular pathways within this axis that contribute to depression-osteoporosis interactions. It details how depression promotes bone loss through sustained hypothalamic-pituitary-adrenal axis activation, sympathetic nervous system overactivity, and chronic low-grade inflammation. This review also explores how bone-derived factors, including osteocalcin, lipocalin 2, and extracellular vesicles, cross the blood-brain barrier to influence brain function by regulating hippocampal neurogenesis, serotonin signaling, and neuroinflammation. This bidirectional communication is modulated by circadian rhythms and genetic factors. Understanding these pathways offers critical insights into the shared pathophysiology and reveals promising therapeutic targets. Interventions such as neuromodulation, customized exercise programs, and novel treatments focusing on bone-derived signals show potential for simultaneously addressing both mood disorders and bone health deterioration. This review emphasizes the need for an integrated system-based approach in clinical care that moves beyond traditional specialty-focused treatment to improve overall health outcomes, particularly for vulnerable elderly individuals.